Epitope-Imprinted Nanoparticles for the Specific Targeting of CD36 in Breast Cancer and Adipocyte Models

Abstract Metabolic coupling between tumor cells and stromal adipocytes represents a critical driver of breast cancer progression, metastatic dissemination, and therapeutic resistance. The scavenger receptor CD36 orchestrates long-chain fatty acid uptake at the tumor−stroma interface, enabling cancer cells to exploit lipid-rich microenvironments. However, precision targeting of CD36 remains challenging due to the limitations of antibody-based approaches. Here, we report the rational design of epitope-imprinted molecularly imprinted polymer nanoparticles (nanoMIPs) engineered to selectively recognize the extracellular domain of CD36 with antibody-mimetic specificity. Fluorescent nanoMIPs demonstrated strict CD36-dependent binding, retained specificity in 3D tumor spheroids, and displayed differentiation-correlated targeting in adipocytes proportional to lipid accumulation and CD36 expression. Importantly, nanoMIPs showed minimal cytotoxicity, enabling the interrogation of metabolic receptor biology without perturbing cellular viability. These findings establish epitope-imprinted nanoMIPs as robust synthetic alternatives to biological ligands for the selective recognition of cell−surface CD36. This work provides a proof of concept for the use of molecularly imprinted nanoparticles as targeting and imaging probes and establishes a foundation for future studies investigating their potential to modulate CD36-mediated metabolic functions.